Search

Abstract Background Filamentous fungi such as Aspergillus niger are well known for their exceptionally high capacity for secretion of proteins, organic acids, and secondary metabolites and they are therefore used in biotechnology as versatile microbial production platforms. However, system-wide insights into their metabolic and secretory capacities are sparse and rational strain improvement approaches are therefore limited. In order to gain a genome-wide view on the transcriptional regulation of the protein secretory pathway of A. niger, we investigated the transcriptome of A. niger when it was forced to overexpression the glaA gene (encoding glucoamylase, GlaA) and secrete GlaA to high level. Results An A. niger wild-type strain and a GlaA over-expressing strain, containing multiple copies of the glaA gene, were cultivated under maltose-limited chemostat conditions (specific growth rate 0.1 h-1). Elevated glaA mRNA and extracellular GlaA levels in the over-expressing strain were accompanied by elevated transcript levels from 772 genes and lowered transcript levels from 815 genes when compared to the wild-type strain. Using GO term enrichment analysis, four higher-order categories were identified in the up-regulated gene set: i) endoplasmic reticulum (ER) membrane translocation, ii) protein glycosylation, iii) vesicle transport, and iv) ion homeostasis. Among these, about 130 genes had predicted functions for the passage of proteins through the ER and those genes included target genes of the HacA transcription factor that mediates the unfolded protein response (UPR), e.g. bipA, clxA, prpA, tigA and pdiA. In order to identify those genes that are important for high-level secretion of proteins by A. niger, we compared the transcriptome of the GlaA overexpression strain of A. niger with six other relevant transcriptomes of A. niger. Overall, 40 genes were found to have either elevated (from 36 genes) or lowered (from 4 genes) transcript levels under all conditions that were examined, thus defining the core set of genes important for ensuring high protein traffic through the secretory pathway. Conclusion We have defined the A. niger genes that respond to elevated secretion of GlaA and, furthermore, we have defined a core set of genes that appear to be involved more generally in the intensified traffic of proteins through the secretory pathway of A. niger. The consistent up-regulation of a gene encoding the acetyl-coenzyme A transporter suggests a possible role for transient acetylation to ensure correct folding of secreted proteins.

Abstract Background Filamentous fungi are confronted with changes and limitations of their carbon source during growth in their natural habitats and during industrial applications. To survive life-threatening starvation conditions, carbon from endogenous resources becomes mobilized to fuel maintenance and self-propagation. Key to understand the underlying cellular processes is the system-wide analysis of fungal starvation responses in a temporal and spatial resolution. The knowledge deduced is important for the development of optimized industrial production processes. Results This study describes the physiological, morphological and genome-wide transcriptional changes caused by prolonged carbon starvation during submerged batch cultivation of the filamentous fungus Aspergillus niger. Bioreactor cultivation supported highly reproducible growth conditions and monitoring of physiological parameters. Changes in hyphal growth and morphology were analyzed at distinct cultivation phases using automated image analysis. The Affymetrix GeneChip platform was used to establish genome-wide transcriptional profiles for three selected time points during prolonged carbon starvation. Compared to the exponential growth transcriptome, about 50% (7,292) of all genes displayed differential gene expression during at least one of the starvation time points. Enrichment analysis of Gene Ontology, Pfam domain and KEGG pathway annotations uncovered autophagy and asexual reproduction as major global transcriptional trends. Induced transcription of genes encoding hydrolytic enzymes was accompanied by increased secretion of hydrolases including chitinases, glucanases, proteases and phospholipases as identified by mass spectrometry. Conclusions This study is the first system-wide analysis of the carbon starvation response in a filamentous fungus. Morphological, transcriptomic and secretomic analyses identified key events important for fungal survival and their chronology. The dataset obtained forms a comprehensive framework for further elucidation of the interrelation and interplay of the individual cellular events involved.

Abstract Background HacA/Xbp1 is a conserved bZIP transcription factor in eukaryotic cells which regulates gene expression in response to various forms of secretion stress and as part of secretory cell differentiation. In the present study, we replaced the endogenous hacA gene of an Aspergillus niger strain with a gene encoding a constitutively active form of the HacA transcription factor (HacACA). The impact of constitutive HacA activity during exponential growth was explored in bioreactor controlled cultures using transcriptomic analysis to identify affected genes and processes. Results Transcription profiles for the wild-type strain (HacAWT) and the HacACA strain were obtained using Affymetrix GeneChip analysis of three replicate batch cultures of each strain. In addition to the well known HacA targets such as the ER resident foldases and chaperones, GO enrichment analysis revealed up-regulation of genes involved in protein glycosylation, phospholipid biosynthesis, intracellular protein transport, exocytosis and protein complex assembly in the HacACA mutant. Biological processes over-represented in the down-regulated genes include those belonging to central metabolic pathways, translation and transcription. A remarkable transcriptional response in the HacACA strain was the down-regulation of the AmyR transcription factor and its target genes. Conclusions The results indicate that the constitutive activation of the HacA leads to a coordinated regulation of the folding and secretion capacity of the cell, but with consequences on growth and fungal physiology to reduce secretion stress.

Abstract Background The filamentous fungus, Aspergillus niger, responds to nutrient availability by modulating secretion of various substrate degrading hydrolases. This ability has made it an important organism in industrial production of secreted glycoproteins. The recent publication of the A. niger genome sequence and availability of microarrays allow high resolution studies of transcriptional regulation of basal cellular processes, like those of glycoprotein synthesis and secretion. It is known that the activities of certain secretory pathway enzymes involved N-glycosylation are elevated in response to carbon source induced secretion of the glycoprotein glucoamylase. We have investigated whether carbon source dependent enhancement of protein secretion can lead to upregulation of secretory pathway elements extending beyond those involved in N-glycosylation. Results This study compares the physiology and transcriptome of A. niger growing at the same specific growth rate (0.16 h-1) on xylose or maltose in carbon-limited chemostat cultures. Transcription profiles were obtained using Affymetrix GeneChip analysis of six replicate cultures for each of the two growth-limiting carbon sources. The production rate of extracellular proteins per gram dry mycelium was about three times higher on maltose compared to xylose. The defined culture conditions resulted in high reproducibility, discriminating even low-fold differences in transcription, which is characteristic of genes encoding basal cellular functions. This included elements in the secretory pathway and central metabolic pathways. Increased protein secretion on maltose was accompanied by induced transcription of > 90 genes related to protein secretion. The upregulated genes encode key elements in protein translocation to the endoplasmic reticulum (ER), folding, N-glycosylation, quality control, and vesicle packaging and transport between ER and Golgi. The induction effect of maltose resembles the unfolded protein response (UPR), which results from ER-stress and has previously been defined by treatment with chemicals interfering with folding of glycoproteins or by expression of heterologous proteins. Conclusion We show that upregulation of secretory pathway genes also occurs in conditions inducing secretion of endogenous glycoproteins – representing a more normal physiological state. Transcriptional regulation of protein synthesis and secretory pathway genes may thus reflect a general mechanism for modulation of secretion capacity in response to the conditional need for extracellular enzymes.

Abstract Background Major changes in climate have been observed in the Arctic and climate models predict further amplification of the enhanced greenhouse effect at high-latitudes leading to increased warming. We propose that warming in the Arctic may affect the annual growth conditions of the cold adapted Arctic charr and that such effects can already be detected retrospectrally using otolith data. Results Inter-annual growth of the circumpolar Arctic charr (Salvelinus alpinus, L.) was analysed in relation to climatic changes observed in the Arctic during the last two decades. Arctic charr were sampled from six locations at Qeqertarsuaq in West Greenland, where climate data have been recorded since 1990. Two fish populations met the criteria of homogeny and, consequently, only these were used in further analyses. The results demonstrate a complex coupling between annual growth rates and fluctuations in annual mean temperatures and precipitation. Significant changes in temporal patterns of growth were observed between cohorts of 1990 and 2004. Conclusion Differences in pattern of growth appear to be a consequence of climatic changes over the last two decades and we thereby conclude that climatic affects short term and inter-annual growth as well as influencing long term shifts in age-specific growth patterns in population of Arctic charr.

Background: Transcatheter aortic valve replacement (TAVR) has become the standard-of-care treatment for a majority of patients with severe, symptomatic aortic stenosis. The postprocedural antithrombotic therapeutic management is still a topic of debate and could affect the incidence of HALT, a phenomenon which can be assessed by 4-dimensional computed tomography (4DCT)., Trial Design: The NOTION-4 trial is a randomized controlled trial comprising TAVR patients with no indication for oral anticoagulant (OAC) therapy, comparing lifelong single antiplatelet therapy (standard arm) versus early 3-month direct oral anticoagulant (DOAC) therapy followed by single antiplateletet therapy (experimental arm). The incidence of HALT and clinical endpoints will be evaluated in both groups at 3 months, 1 year and 5 years after randomization. The primary endpoint is the number of patients with at least 1 bioprosthetic aortic valve leaflet with HALT as assessed by cardiac 4DCT imaging at 1 year. The trial is powered for superiority testing and started enrollment in 2021. In total, 324 patients will be included. The last patient is expected to be enrolled by the end of 2024 and the primary endpoint is to be presented in 2026., Conclusion and Perspective: The NOTION-4 trial aims to study whether an early 3-month DOAC therapy after TAVR can result in a sustained lower incidence of HALT in transcatheter aortic valves. This trial holds the potential to give valuable insights into whether early OAC therapy should be integrated in future guidelines for post-TAVR antithrombotic therapeutic management., Trial Registration: NOTION-4, ClinicalTrials.gov ID NCT06449469, https://clinicaltrials.gov/study/NCT06449469., Competing Interests: Disclosures None reported., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Aims: Transcatheter aortic valve implantation (TAVI) has become the first choice to treat older patients with severe symptomatic aortic stenosis (AS). This study aimed to compare TAVI with surgery in low-risk patients ≤75 years of age, including both tricuspid and bicuspid AS., Methods: The Nordic Aortic Valve Intervention (NOTION)-2 trial enrolled and 1:1 randomized low-risk patients aged ≤75 years with severe symptomatic AS to TAVI or surgery. The primary endpoint was a composite of all-cause mortality, stroke, or rehospitalization (related to the procedure, valve, or heart failure) at 12 months., Results: A total of 370 patients were enrolled with a mean age of 71.1 years and a median Society of Thoracic Surgeons risk score of 1.1%. A total of 100 patients had bicuspid AS. The 1-year incidence of the primary endpoint was 10.2% in the TAVI group and 7.1% in the surgery group [absolute risk difference 3.1%; 95% confidence interval (CI), -2.7% to 8.8%; hazard ratio (HR) 1.4; 95% CI, 0.7-2.9; P = .3]. Patients with TAVI, when compared to surgery, had lower risk of major bleeding and new-onset atrial fibrillation and higher risk of non-disabling stroke, permanent pacemaker implantation, and moderate or greater paravalvular regurgitation. The risk of the primary composite endpoint was 8.7% and 8.3% in patients with tricuspid AS (HR 1.0; 95% CI, 0.5-2.3) and 14.3% and 3.9% in patients with bicuspid AS (HR 3.8; 95% CI, 0.8-18.5) treated with TAVI or surgery, respectively (P for interaction = .1)., Conclusions: Among low-risk patients aged ≤75 years with severe symptomatic AS, the rate of the composite of death, stroke, or rehospitalization at 1 year was similar between TAVI and surgery. Transcatheter aortic valve implantation outcomes in young bicuspid AS patients warrant caution and should be further investigated. (NOTION-2, ClinicalTrials.gov, NCT02825134)., Trial Registration Number: ClinicalTrials.gov NCT02825134., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: The congenital heart disease (CHD) population is growing and aging. We aim to examine the impact by describing the temporal trend and causes of lifetime hospitalization burden among the CHD population., Methods and Results: From the Danish National Patient Registry, 23 141 patients with CHD and their hospitalizations from 1977 to 2018 were identified, excluding patients with extracardiac malformation. Patients with CHD were categorized into major CHD and minor CHD, and each patient was matched with 10 controls by sex and year of birth. The rate of all-cause hospitalization increased over time from 28.3 to 36.4 hospitalizations per 100 person-years (PY) with rate difference (RD) per decade of 2.5 (95% CI, 2.0-3.1) hospitalizations per 100 PY for the patients with CHD, compared with the increase from 10.8 to 17.0 per 100 PY (RD per decade, 2.0 [95% CI, 1.8-2.2] per 100 PY) for the control group (RD for CHD versus control, P =0.08). The all-cause hospitalization rate remained constant for the major CHDs (RD per decade, -0.2 [95% CI, -1.2 to 0.9] per 100 PY) but increased for the minor CHDs (RD per decade, 5.2 [95% CI, 4.3-6.0] per 100 PY). For all patients with CHD, the cardiovascular hospitalization rate remained constant over time (RD per decade, 0.2 [95% CI, -0.3 to 0.6] per 100 PY) whereas the noncardiovascular hospitalization rate increased (RD per decade, 2.1 [95% CI, 1.6-2.7] per 100 PY). The length of all-cause hospital stays for all patients with CHD decreased from 2.7 (95% CI, 2.6-2.8) days per PY in 1977 to 1987 to 1.6 (95% CI, 1.6-1.7) days per PY in 2008 to 2018., Conclusions: Compared with previous decades, patients with CHD have an increasing hospitalization rate, similar to the general population, but a decreasing length of hospital stay. The increase in hospitalization rate was driven by noncardiovascular hospitalizations, with the patients with minor CHD being the key contributor to the increasing rate.

Background: Limited data are available on transcatheter patent foramen ovale (PFO) closure outcomes in the elderly., Aims: Through this study, we aimed to determine the incidence and predictors of adverse events (recurrent cerebrovascular events [CVE] and atrial fibrillation [AF]) post-PFO closure in older patients with cryptogenic events., Methods: This multicentre international study included patients over 60 years undergoing PFO closure for cryptogenic thromboembolic events. A dedicated database compiled baseline, procedural, and follow-up data. Competing risk and adjusted outcome predictor analyses were conducted., Results: A total of 689 patients were included (median age 65 years, 41.2% female, mean Risk of Paradoxical Embolism [RoPE] score 4.5). The procedural success rate was 99.4%. After a median follow-up of 2 (interquartile range 1-5) years, 66 patients (9.6%) had died. CVE and stroke rates were 1.21 and 0.55 per 100 patient-years, respectively. Diabetes (hazard ratio [HR] 3.89, 95% confidence interval [CI]: 1.67-9.07; p=0.002) and atrial septal aneurysm (ASA; HR 5.25, 95% CI: 1.56-17.62; p=0.007) increased the CVE risk. New-onset AF occurred at a rate of 3.30 per 100 patient-years, with 51.3% within one month post-procedure. Older age (HR 1.05 per year, 95% CI: 1.00-1.09; p=0.023) and the absence of hypertension (HR 2.04, 95% CI: 1.19-3.57; p=0.010) were associated with an increased risk of AF., Conclusions: Older patients undergoing PFO closure had a relatively low rate of CVE and new-onset AF after a median follow-up of 2 years. The presence of diabetes, ASA, and a more advanced age determined an increased risk of adverse clinical events. These factors may be considered in the clinical decision-making process regarding PFO closure in this challenging population.

Aims: Despite rehospitalization being common after transcatheter aortic valve implantation (TAVI), an in-depth analysis on this topic is missing. This study sought to report on the incidence, predictors, and prognostic impact of rehospitalization within 1 year following TAVI., Methods and Results: All consecutive patients treated with TAVI between 2016 and 2020 in East Denmark were included. Medical records of all patients were reviewed to validate rehospitalizations up to 1 year after discharge from the index admission. The study population consisted of 1397 patients, of whom 615 (44%) had an unplanned rehospitalization within the first year post-TAVI. The rehospitalization incidence rate was three-fold higher in the early period (within 30 days) compared with the late period (30 days to 1 year; 2.5 vs. 0.8 per patient-year, respectively; P < 0.001). Predictors of early unplanned rehospitalization were procedure-related complications and prior stroke, whereas late unplanned rehospitalization was associated with preexisting comorbidities. Predictors of heart failure (HF) rehospitalization included ischaemic heart disease, the extent of cardiac damage, atrial fibrillation, and New York Heart Association class at baseline. HF rehospitalization within 30 days and 1 year post-TAVI was associated with a markedly increased 1- and 5-year mortality risk [hazard ratio (HR) of 4.3 and 3.2 for 1-year mortality and HR of 3.2 and 2.9 for 5-year mortality, respectively; P< 0.001]., Conclusions: Rehospitalization after TAVI is frequent in real-world practice. Early rehospitalization is mostly procedure related, whereas late rehospitalization is related to preexisting comorbidities. HF rehospitalization is associated with poor long-term survival and could be validated as a prognostically relevant endpoint for TAVI trials., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Introduction: Overweight and obesity constitute a major concern among patients treated at forensic psychiatric departments. The present clinical feasibility study aimed at investigating the extent to which glucagon-like peptide 1 receptor agonist (GLP-1RA) treatment with once-daily liraglutide 3.0 mg could be a feasible pharmacological treatment of these conditions in patients with schizophrenia spectrum disorders hospitalised in forensic psychiatry., Methods: The 26-week, open-label feasibility study included participants aged 18-65 years diagnosed with a severe mental illness and hospitalised at a forensic psychiatric department. At the time of inclusion, all participants fulfilled the indication for using liraglutide as a treatment for overweight and obesity. Participants' baseline examinations were followed by a 26-week treatment period with liraglutide injection once daily according to a fixed uptitration schedule of liraglutide, with a target dose of 3.0 mg. Each participant attended seven visits to evaluate the efficacy and adverse events. The primary endpoint was the number of "completers", with adherence defined as >80% injections obtained in the period, weeks 12-26. Determining whether liraglutide is a feasible treatment was pre-defined to a minimum of 75% completers., Results: Twenty-four participants were included in the study. Sex, male = 19 (79.2%). Mean age: 42.3 [25th and 75th percentiles: 39.1; 48.4] years; body mass index (BMI): 35.7 [31.7; 37.5] kg/m 2 ; glycated haemoglobin (HbA1c): 37 [35; 39] mmol/mol. Eleven out of 24 participants (46%) completed the study. For the completers, the median net body weight loss after 26 weeks of participation was -11.4 kg [-15.4; -5.9]. The net difference in HbA1C and BMI was -2.0 mmol/mol [-4; -1] and -3.6 kg/m 2 [-4.7; -1.8], respectively. The weight change and reduction in HbA1c and BMI were all statistically significant from baseline., Conclusion: The study did not confirm our hypothesis that liraglutide is a feasible treatment for a minimum of 75% of the patients initiating treatment with liraglutide while hospitalised in a forensic psychiatric department. The high dropout rate may be due to the non-naturalistic setting of the clinical trial. For the proportion of patients compliant with the medication, liraglutide 3.0 mg was an efficient treatment for overweight., (© 2024 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

Background: Atrial fibrillation (AF) is one of the most common complications after cardiac surgery. New-onset post-operative AF may signal an elevated risk of AF and associated outcomes in long-term follow-up. We aimed to estimate the rate of AF recurrence as detected by an implantable loop recorder (ILR) in patients experiencing post-operative AF within 30 days after cardiac surgery., Methods: We searched MEDLINE, Embase and Cochrane CENTRAL to April 2023 for studies of adults who did not have known AF, experienced new-onset AF within 30 days of cardiac surgery and received an ILR. We pooled individual participant data on timing of AF recurrence using a random-effects model with a frailty model applied to a Cox proportional hazard analysis., Results: From 8671 citations, 8 single-centre prospective cohort studies met eligibility criteria. Data were available from 185 participants in 7 studies, with a median follow-up of 1.7 (IQR: 1.3-2.8) years. All included studies were at a low risk of bias. Pooled AF recurrence rates following 30 post-operative days were 17.8% (95% CI 11.9%-23.2%) at 3 months, 24.4% (17.7%-30.6%) at 6 months, 30.1% (22.8%-36.7%) at 12 months and 35.3% (27.6%-42.2%) at 18 months., Conclusions: In patients who experience new-onset post-operative AF after cardiac surgery, AF recurrence lasting at least 30 s occurs in approximately 1 in 3 in the first year after surgery. The optimal frequency and modality to use for monitoring for AF recurrence in this population remain uncertain., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Groundwater contamination is a threat to drinking water resources and ecosystems. Remediation by injection of chemical reagents into the aquifer may be preferred to excavation to reduce cost and environmental footprint. Yet, successful remediation requires complete contact between contamination and reagents. Subsurface heterogeneities are often responsible for diffusion into low-permeable zones, which may inhibit this contact. Monitoring the spatial distribution of injected reagents over time is crucial to achieve complete interaction. Source zone contamination at megasites is particularly challenging to remediate and monitor due to the massive scale and mixture of contaminants. Source zone remediation at Kærgård Plantation megasite (Denmark) is monitored here, with a new methodology, using high-resolution cross-borehole electrical resistivity tomography (XB-ERT) imaging calibrated by chemical analyses on groundwater samples. At this site, high levels of toxic non-aqueous phase liquids (NAPL) are targeted by in-situ chemical oxidation using activated persulfate. It may take numerous injection points with extensive injection campaigns to distribute reagents, which requires an understanding of how reagent may transport within the aquifer. A geophysical (XB-ERT) monitoring network of unprecedented size was installed to identify untreated zones and help manage the remediation strategy. The combination of spatially continuous geophysical information with discrete but precise chemical information, allowed detailed monitoring of sulfate distribution, produced during persulfate activation. Untreated zones identified in the first remediation campaign were resolved in the second campaign. The monitoring allowed adjusting the number of injection screens and the injection strategy from one campaign to the next, which resulted in better persulfate distribution and contaminant degradation in the second campaign. Furthermore, geophysical transects repeated over the timespan of a remediation campaign allowed high-resolution time-lapse imaging of reagent transport, which could in the future improve the predictability of transport models, compared to only using on a-priori assumptions of the hydraulic conductivity field., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Transcatheter aortic valve implantation (TAVI) has become a viable treatment option for patients with severe aortic valve stenosis across a broad range of surgical risk. The Nordic Aortic Valve Intervention (NOTION) trial was the first to randomize patients at lower surgical risk to TAVI or surgical aortic valve replacement (SAVR). The aim of the present study was to report clinical and bioprosthesis outcomes after 10 years., Methods: The NOTION trial randomized 280 patients to TAVI with the self-expanding CoreValve (Medtronic Inc.) bioprosthesis (n = 145) or SAVR with a bioprosthesis (n = 135). The primary composite outcome was the risk of all-cause mortality, stroke, or myocardial infarction. Bioprosthetic valve dysfunction (BVD) was classified as structural valve deterioration (SVD), non-structural valve dysfunction (NSVD), clinical valve thrombosis, or endocarditis according to Valve Academic Research Consortium-3 criteria. Severe SVD was defined as (i) a transprosthetic gradient of 30 mmHg or more and an increase in transprosthetic gradient of 20 mmHg or more or (ii) severe new intraprosthetic regurgitation. Bioprosthetic valve failure (BVF) was defined as the composite rate of death from a valve-related cause or an unexplained death following the diagnosis of BVD, aortic valve re-intervention, or severe SVD., Results: Baseline characteristics were similar between TAVI and SAVR: age 79.2 ± 4.9 years and 79.0 ± 4.7 years (P = .7), male 52.6% and 53.8% (P = .8), and Society of Thoracic Surgeons score < 4% of 83.4% and 80.0% (P = .5), respectively. After 10 years, the risk of the composite outcome all-cause mortality, stroke, or myocardial infarction was 65.5% after TAVI and 65.5% after SAVR [hazard ratio (HR) 1.0; 95% confidence interval (CI) 0.7-1.3; P = .9], with no difference for each individual outcome. Severe SVD had occurred in 1.5% and 10.0% (HR 0.2; 95% CI 0.04-0.7; P = .02) after TAVI and SAVR, respectively. The cumulative incidence for severe NSVD was 20.5% and 43.0% (P < .001) and for endocarditis 7.2% and 7.4% (P = 1.0) after TAVI and SAVR, respectively. No patients had clinical valve thrombosis. Bioprosthetic valve failure occurred in 9.7% of TAVI and 13.8% of SAVR patients (HR 0.7; 95% CI 0.4-1.5; P = .4)., Conclusions: In patients with severe AS and lower surgical risk randomized to TAVI or SAVR, the risk of major clinical outcomes was not different 10 years after treatment. The risk of severe bioprosthesis SVD was lower after TAVR compared with SAVR, while the risk of BVF was similar., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Cardiac damage has gained increasing attention as a valid prognostic marker of mortality after transcatheter aortic valve replacement (TAVR). However, studies investigating the possible association between cardiac damage and hospitalization burden in TAVR patients are lacking., Aims: This study aimed to investigate the impact of baseline cardiac damage on the hospitalization burden before, during, and after TAVR in an all-comers population., Methods: All consecutive patients who underwent TAVR between 2016 and 2020 were included. Electronic medical records of all patients were examined to validate cardiovascular (CV) and heart failure (HF) related hospitalizations from 6 months before to 1 year after TAVR. Baseline cardiac damage was defined according to the staging classification by Généreux et al. RESULTS: Among 1397 TAVR patients, 94 (6.7%) had stage 0, 368 (26.4%) stage 1, 736 (52.7%) stage 2, 115 (8.2%) stage 3, and 84 (6.0%) stage 4 cardiac damage. Patients with more advanced cardiac damage at baseline had more HF hospitalizations within 6 months before TAVR (p < 0.01) and with a longer length of stay (LoS) (p < 0.01). Regarding the index TAVR admission, there was no difference in procedure time (p = 0.26) or LoS (p = 0.18) between groups. Still, TAVR patients with more advanced baseline cardiac damage had a higher risk of CV and HF rehospitalization after TAVR (p < 0.05)., Conclusions: Baseline cardiac damage in patients undergoing TAVR has an impact on the pre- and post-procedural cardiovascular hospitalization burden. However, the cardiac damage status does not affect the TAVR procedure time or index TAVR admission length of stay., (© 2024 The Authors. Catheterization and Cardiovascular Interventions published by Wiley Periodicals LLC.)

Background: Robust data on changes in pulmonary valve replacement (PVR) procedural volume and predictors of bioprosthetic pulmonary valve (BPV) durability in patients with tetralogy of Fallot (TOF) are scarce., Objectives: This study sought to assess temporal trends in PVR procedural volume and BPV durability in a nationwide, retrospective TOF cohort., Methods: Data were obtained from patient records. Robust linear regression was used to assess temporal trends in PVR procedural volume. Piecewise exponential additive mixed models were used to estimate BPV durability, defined as the time from implantation to redo PVR with death as a competing risk, and to assess risk factors for reduced durability., Results: In total, 546 PVR were performed in 384 patients from 1976 to 2021. The annual number of PVR increased from 0.4 to 6.0 per million population (P < 0.001). In the last decade, the transcatheter PVR volume increased by 20% annually (P < 0.001), whereas the surgical PVR volume did not change significantly. The median BPV durability was 17 years (Q1: 10-Q3: 10 years-not applicable). There was no significant difference in the durability of different BPV after adjustment for confounders. Age at PVR (HR: 0.78 per 10 years from <1 year; 95% CI: 0.63-0.96; P = 0.02) and true inner valve diameter (9-17 mm vs 18-22 mm HR: 0.40; 95% CI: 0.22-0.73; P = 0.003 and 18-22 mm vs 23-30 mm HR: 0.59; 95% CI: 0.25-1.39; P = 0.23) were associated with reduced BPV durability in multivariate models., Conclusions: The PVR procedural volume has increased over time, with a greater increment in transcatheter than surgical PVR during the last decade. Younger patient age at PVR and a smaller true inner valve diameter predicted reduced BPV durability., Competing Interests: Funding Support and Author Disclosures This study was funded by the Danish Heart Foundation, Copenhagen, Denmark, and the Novo Nordisk Foundation, Hellerup, Denmark. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: This study aims to compare valve durability between transcatheter aortic valve implantation (TAVI) and surgical aortic valve replacement (SAVR)., Methods: We conducted a systematic review and meta-analysis using data from randomized controlled trials (RCTs). The primary outcome was structural valve deterioration (SVD). Secondary outcomes were bioprosthetic valve failure, reintervention, effective orifice area (EOA), mean pressure gradient, and moderate-severe aortic regurgitation (AR, transvalvular and/or paravalvular)., Results: Twenty-five publications from seven RCTs consisting of 7,970 patients were included in the analysis with follow-up ranges of 2-8 years. No significant difference was found between the two groups with regard to SVD [odds ratio (OR) 0.72; 95% CI: 0.25-2.12]. The TAVI group was reported to exhibit a statistically significant higher risk of reintervention (OR 2.03; 95% CI: 1.34-3.05) and a moderate-severe AR (OR 6.54; 95% CI: 3.92-10.91) compared with the SAVR group. A trend toward lower mean pressure gradient in the TAVI group [(mean difference (MD) -1.61; 95% CI: -3.5 to 0.28)] and significant higher EOA (MD 0.20; 95% CI: 0.08-0.31) was noted., Conclusion: The present data indicate that TAVI provides a comparable risk of SVD with favorable hemodynamic profile compared with SAVR. However, the higher risk of significant AR and reintervention was demonstrated., Systematic Review Registration: PROSPERO (CRD42022363060)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Lerman, Levi, Jørgensen, Søndergaard, Talmor-Barkan and Kornowski.)

Transcatheter aortic valve implantation (TAVR) is the first therapeutic option for elderly patients with severe symptomatic aortic stenosis, and indications are steadily expanding to younger patients and subjects with lower surgical risk and longer life expectancy. Commissural alignment between native and transcatheter valves facilitates coronary access after TAVR and is thus considered a procedural goal, allowing long-term management of coronary artery disease. Moreover, commissural alignment may potentially have a positive impact on transvalvular hemodynamic and valve durability. This review focus on technical hints to achieve commissural alignment and current evidence for different transcatheter aortic valves.

Aims: Additional randomized clinical trial (RCT) data comparing transcatheter aortic valve implantation (TAVI) with surgical aortic valve replacement (SAVR) is available, including longer term follow-up. A meta-analysis comparing TAVI to SAVR was performed. A pragmatic risk classification was applied, partitioning lower-risk and higher-risk patients., Methods and Results: The main endpoints were death, strokes, and the composite of death or disabling stroke, occurring at 1 year (early) or after 1 year (later). A random-effects meta-analysis was performed. Eight RCTs with 8698 patients were included. In lower-risk patients, at 1 year, the risk of death was lower after TAVI compared with SAVR [relative risk (RR) 0.67; 95% confidence interval (CI) 0.47 to 0.96, P = 0.031], as was death or disabling stroke (RR 0.68; 95% CI 0.50 to 0.92, P = 0.014). There were no differences in strokes. After 1 year, in lower-risk patients, there were no significant differences in all main outcomes. In higher-risk patients, there were no significant differences in main outcomes. New-onset atrial fibrillation, major bleeding, and acute kidney injury occurred less after TAVI; new pacemakers, vascular complications, and paravalvular leak occurred more after TAVI., Conclusion: In lower-risk patients, there was an early mortality reduction with TAVI, but no differences after later follow-up. There was also an early reduction in the composite of death or disabling stroke, with no difference at later follow-up. There were no significant differences for higher-risk patients. Informed therapy decisions may be more dependent on the temporality of events or secondary endpoints than the long-term occurrence of main clinical outcomes., Competing Interests: Conflict of interest: A.D.A. reports honoraria and sponsorship from Medtronic and Bayer. M.M. was supported by a grant from the National Institutes of Health/National Heart, Lung, and Blood Institute to Columbia University Irving Medical Center (T32 HL007854). C.M.C. reports speaker fees from Philips Volcano. M.J.M. has served as a co-principal investigator for Edwards Lifesciences and Abbott; and as a study chair for Medtronic. M.J.R. served as national surgical PI on SURTAVI, Evolut Low-Risk, Reprise III, Acurate, Portico NG and Vantage and received research support from Medtronic, Boston Scientific, Abbott Medical, Gore. R.R.M. has received research grants from Edwards Lifesciences, Abbott, Medtronic, and Boston Scientific; has served as national Principal Investigator for Portico (Abbott) and Acurate (Boston Scientific) U.S. investigation device exemption trials; has received personal proctoring fees from Edwards Lifesciences; and has received travel support from Edwards Lifesciences, Abbott, and Boston Scientific. V.H.T. is an advisor or research support from Abbott Vascular, Cyrolife, Atricure, Edwards Lifesciences, Shockwave, and JenaValve; and has received consulting fees from Edwards Lifesciences, Boston Scientific, Abbott, Gore Vascular, and JenaValve. L.S. has received consultant fees and/or institutional research grants from Abbott, Boston Scientific, Edwards Lifesciences, Medtronic, Symetis, and SMT. N.V.M. has received institutional research grants from Abbott, ACIST Medical Systems, Boston Scientific, Biotronik, Medtronic, Edwards Lifesciences, Abiomed, Daiichi Sankyo, Pie Medical and PulseCath. J.K.F. is a consultant for Edwards Lifesciences and Medtronic and receives grant support from Edwards Lifesciences and Medtronic. M.B.L. has received research support to his institution from Edwards Lifesciences, Medtronic, Boston Scientific, and Abbott; has served on Advisory Boards for Medtronic, Boston Scientific, Gore, Meril Lifescience, and Abbott; and has served as the Co-Principal Investigator of the PARTNER 3 trial (Edwards Lifesciences, no direct compensation)., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: To assess temporal changes in the surgical management of patients with tetralogy of Fallot including the timing of interventions, surgical techniques, reinterventions and survival in a nationwide cohort., Methods: Patients with tetralogy of Fallot in Denmark were divided into 3 eras based on their year of birth: early (1977-1991), intermediate (1992-2006) and late (2007-2021)., Results: The cohort consisted of 745 patients. Median follow-up was 21.2 years (13.7-30.5). There was a temporal trend towards less shunt palliation (-0.3% per year, 95% CI -0.05 to -0.1). Median age at intracardiac repair was 2.9 years (1.8-5.0), 0.8 years (0.5-1.3) and 0.5 years (0.4-0.7) (P < 0.001) in the early, intermediate and late era, respectively. There was a temporal trend towards less valve-sparing repair (-0.7% per year, 95% CI -0.5 to -1.0) and more repair with transannular patches (0.7% per year, 95% CI 0.5-1.0). Survival at 10 years was 79% (64-76), 90% (87-93) and 95% (92-98) (P < 0.001) and pulmonary valve replacement within the first 10 years after intracardiac repair was performed in 3% (1-6), 12% (8-16) and 21% (13-29) (P < 0.001) in the early, intermediate and late era, respectively., Conclusions: There was a temporal trend towards less shunt palliation and intracardiac repair at a younger age with more use of transannular patches. While survival throughout childhood and adolescence has improved, more patients undergo pulmonary valve replacement during the first 10 years after intracardiac repair., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Use of a right-left (R-L) cusp overlap view for transcatheter aortic valve replacement (TAVR) with self-expanding valves has recently been proposed aiming to reduce permanent pacemaker implantation (PPMI). An objective, data-driven explanation for this observation is missing., Aims: To assess the impact of different implantation techniques on the risk of PPMI following TAVR with the Portico/Navitor TM transcatheter heart valve (THV; Abbott)., Methods: A TAVR-population treated with Portico/Navitor TM had the THV implanted in a right versus left anterior oblique (RAO/LAO) fluoroscopic view with no parallax in the delivery system. The impact of these different implantation views on the spatial relationship between THV and native aortic annulus and the risk of conduction disturbances and PPMI after TAVR was studied., Results: A total of 366 matched TAVR patients were studied: 183 in the RAO group and 183 in the LAO group. The degree of aortic annulus plane tilt was significantly smaller in the RAO versus LAO group (median: 0° vs. 23°, p < 0.001), with no plane tilt in 105 out of 183 cases (57.3%) in the RAO group. At 30 days after TAVR, the overall PPMI and guideline-directed PPMI rates were 12.6% versus 18.0% (p = 0.15) and 8.2% versus 15.3% (p = 0.04) in the RAO versus LAO group, respectively., Conclusions: Use of a R-L cusp overlap (RAO-caudal) view for implantation of the Portico/Navitor TM valve results in less tilt of the native aortic annulus plane and a clear trend toward a lower 30-day PPMI rate as compared to TAVR using the conventional LAO implantation view., (© 2022 The Authors. Catheterization and Cardiovascular Interventions published by Wiley Periodicals LLC.)

Background Little is known about the cause of death (CoD) in patients with transposition of the great arteries palliated with a Mustard or Senning procedure. The aim was to describe the CoD for patients with the Mustard and Senning procedure during short- (<10 years), mid- (10-20 years), and long-term (>20 years) follow-up after the operation. Methods and Results This is a retrospective, descriptive multicenter cohort study including all Nordic patients (Denmark, Finland, Norway, and Sweden) who underwent a Mustard or Senning procedure between 1967 and 2003. Patients who died within 30 days after the index operation were excluded. Among 968 patients with Mustard/Senning palliated transposition of the great arteries, 814 patients were eligible for the study, with a mean follow-up of 33.6 years. The estimated risk of all-cause mortality reached 36.0% after 43 years of follow-up, and the risk of death was highest among male patients as compared with female patients ( P =0.004). The most common CoD was sudden cardiac death (SCD), followed by heart failure/heart transplantation accounting for 29% and 27%, respectively. During short-, mid-, and long-term follow-up, there was a change in CoD with SCD accounting for 23.7%, 46.6%, and 19.0% ( P =0.002) and heart failure/heart transplantation 18.6%, 22.4%, and 46.6% ( P =0.0005), respectively. Conclusions Among patients corrected with Mustard or Senning transposition of the great arteries, the most common CoD is SCD followed by heart failure/heart transplantation. The CoD changes as the patients age, with SCD as the most common cause in adolescence and heart failure as the dominant cause in adulthood. Furthermore, the risk of all-cause mortality, SCD, and death attributable to heart failure or heart transplantation was increased in men >10 years after the Mustard/Senning operation.

Background: There are limited data on the association of membranous septum (MS) morphology and transcatheter heart valve (THV) implantation depth, and the development of new conduction abnormalities (CA) after transcatheter aortic valve implantation (TAVI)., Aims: The aim of this study was to describe the morphology of the MS and predict the risk of new CA after TAVI based on the MS morphology and THV implantation depth., Methods: Based on preprocedural CT scans, the MS depth was measured for every 25% of the entire MS width in 272 TAVI patients without preprocedural bundle branch block (BBB) or pacemaker. Post-procedural CT scans for THV implantation depth assessment were available in 130 of these patients., Results: The MS depth was a median of 2.5 mm (IQR 1.4-3.8) deeper at the posterior edge when compared to the anterior edge of the MS. New CA developed in 7.1% of patients in whom the THV did not cross the lower MS border at its anterior edge (3.6% with new BBB and high degree CA, respectively), in 18.8% of patients (15.6% with new BBB and 3.1% with new high-degree CA) where the THV overlapped the lower MS border by <2.5 mm and in 47.1% of patients (24.3% with new BBB and 22.9% with new high-degree CA) with THV overlap of the lower MS border by ≥2.5 mm., Conclusions: The difference of the MS depth and THV implantation depth measured at the anterior edge of the MS predicted new CA after TAVI.

Patients with heart failure with preserved ejection fraction (HFpEF) constitutes a considerable sized population like that of subjects with heart failure with reduced ejection fraction. The symptoms include exercise induced dyspnoea and fatigue besides an increased mortality rate when compared to the general population. There is limited evidence of benefit from pharmacological therapy. A main pathophysiological mechanism is a left ventricular filling pressure that might be near to normal during resting conditions but increases during exercise leading to pulmonary congestion. Based on observations like the apparent lesser symptomatology in patients with combined mitral valve stenosis and atrial septal defect (Lutembacher syndrome) when compared to patients with isolated mitral valve stenosis, several Inter-Atrial Shunt Devices (IASD) have been developed with the intent to unload the pressure in the left atrium by creating a shunt into the right atrium. Smaller studies have found that the IASDs reduce the left ventricular filling pressure during exercise and increase the functional status of patients both subjectively and objectively with reported low rates of complications. These devices are undergoing further investigations and might prove to be a new paradigm in the treatment of patients with HFpEF., Competing Interests: Conflict of Interest: The authors have no financial conflicts of interest., (Copyright © 2022. Korean Society of Heart Failure.)

Aims: The aims of the study were to compare clinical outcomes and valve durability after 8 years of follow-up in patients with symptomatic severe aortic valve stenosis at low surgical risk treated with either transcatheter aortic valve implantation (TAVI) or surgical aortic valve replacement (SAVR)., Methods and Results: In the NOTION trial, patients with symptomatic severe aortic valve stenosis were randomized to TAVI or SAVR. Clinical status, echocardiography, structural valve deterioration, and failure were assessed using standardized definitions. In total, 280 patients were randomized to TAVI (n = 145) or SAVR (n = 135). Baseline characteristics were similar, including mean age of 79.1 ± 4.8 years and a mean STS score of 3.0 ± 1.7%. At 8-year follow-up, the estimated risk of the composite outcome of all-cause mortality, stroke, or myocardial infarction was 54.5% after TAVI and 54.8% after SAVR (P = 0.94). The estimated risks for all-cause mortality (51.8% vs. 52.6%; P = 0.90), stroke (8.3% vs. 9.1%; P = 0.90), or myocardial infarction (6.2% vs. 3.8%; P = 0.33) were similar after TAVI and SAVR. The risk of structural valve deterioration was lower after TAVI than after SAVR (13.9% vs. 28.3%; P = 0.0017), whereas the risk of bioprosthetic valve failure was similar (8.7% vs. 10.5%; P = 0.61)., Conclusions: In patients with severe aortic valve stenosis at low surgical risk randomized to TAVI or SAVR, there were no significant differences in the risk for all-cause mortality, stroke, or myocardial infarction, as well as the risk of bioprosthetic valve failure after 8 years of follow-up., Clinical Trial Registration: URL: http://www.ClinicalTrials.gov. Unique identifier: NCT01057173., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Early discharge after transcatheter aortic valve implantation (TAVI) may potentially impact post-procedural safety of the patient. The study aim was to compare safety of TAVI in patients planned for fast track hospital stay with patients planned for standard hospital stay., Methods and Results: All-comers patients undergoing transfemoral TAVI between 2011 and 2017 were allocated to two matched groups depending whether the procedure was performed before or after transition from standard to fast track course. Data on vital status and hospitalizations were obtained through national registries. Three hundred and nineteen matched pairs were eligible for analysis. The median length of post-procedural stay was 3 days (IQR: 2-4) for patients in the fast track group compared to 6 days (IQR: 4-8) in the standard approach group (p < .0001). There was no difference in all-cause mortality between groups at 30-day (1.3% vs. 1.9%, p = .52) or 90-day follow-up (2.9% vs. 4.1%, p = .42). There was no difference in the risk of new permanent pacemaker implantation (PPI) in pacemaker naïve patients between groups at 30-day (15.8% vs. 21.2%, p = .16) or 90-day follow-up (15.8% vs. 21.9%, p = .12). There was no difference in the rate of rehospitalization between groups between discharge and 90-day follow-up (2.09 per patient-year vs. 2.09 per patient-year, p = .99)., Conclusions: Early discharge in an all-comers population undergoing transfemoral TAVI is safe with regards to all-cause mortality, need for PPI, and rehospitalization., (© 2020 Wiley Periodicals LLC.)

Objectives: We aimed to evaluate the effect of transcatheter aortic valve implantation (TAVI) approaches on mortality and identify effect modifiers and predictors for mortality., Background: Alternative access routes to transfemoral (TF) TAVI include the surgical intra-thoracic direct-aortic (DA) and transapical (TA) approach. TA TAVI has been associated with a higher mortality rate. We hypothesized that this is related to effect modifiers, in particular the left ventricular ejection fraction (LVEF)., Methods: This multicentre study derived its data from prospective registries. To adjust for confounders, we used propensity-score based, stabilized inverse probability weighted Cox regression models., Results: In total, 5,910 patients underwent TAVI via TF (N = 4,072), DA (N = 524), and TA (N = 1,314) access. Compared to TF, 30-day mortality was increased among DA (HR 1.87, 95%CI 1.26-2.78, p = .002) and TA (HR 3.34, 95%CI 2.28-4.89, p < .001) cases. Compared to TF, 5-year mortality was increased among TA cases (HR 1.50, 95%CI 1.24-1.83, p < .001). None of the variables showed a significant interaction between the approaches and mortality. An impaired LVEF (≤35%) increased mortality in all approaches., Conclusions: The surgical intra-thoracic TA and DA TAVI are both associated with a higher 30-day mortality than TF TAVI. TA TAVI is associated with a higher 5-year mortality than TF TAVI. The DA approach may therefore have some advantages over the TA approach when TF access is not feasible., (© 2021 Wiley Periodicals LLC.)

Aims: The clinical impact of new-onset persistent left bundle branch block (NOP-LBBB) and permanent pacemaker implantation (PPI) on transcatheter aortic valve replacement (TAVR) recipients remains controversial. We aimed to evaluate the impact of (i) periprocedural NOP-LBBB and PPI post-TAVR on 1-year all-cause death, cardiac death, and heart failure hospitalization and (ii) NOP-LBBB on the need for PPI at 1-year follow-up., Methods and Results: We performed a systematic search from PubMed and EMBASE databases for studies reporting raw data on 1-year clinical impact of NOP-LBBB or periprocedural PPI post-TAVR. Data from 30 studies, including 7792 patients (12 studies) and 42 927 patients (21 studies) for the evaluation of the impact of NOP-LBBB and PPI after TAVR were sourced, respectively. NOP-LBBB was associated with an increased risk of all-cause death [risk ratio (RR) 1.32, 95% confidence interval (CI) 1.17-1.49; P < 0.001], cardiac death (RR 1.46, 95% CI 1.20-1.78; P < 0.001), heart failure hospitalization (RR 1.35, 95% CI 1.05-1.72; P = 0.02), and PPI (RR 1.89, 95% CI 1.58-2.27; P < 0.001) at 1-year follow-up. Periprocedural PPI after TAVR was associated with a higher risk of all-cause death (RR 1.17, 95% CI 1.11-1.25; P < 0.001) and heart failure hospitalization (RR 1.18, 95% CI 1.03-1.36; P = 0.02). Permanent pacemaker implantation was not associated with an increased risk of cardiac death (RR 0.84, 95% CI 0.67-1.05; P = 0.13)., Conclusion: NOP-LBBB and PPI after TAVR are associated with an increased risk of all-cause death and heart failure hospitalization at 1-year follow-up. Periprocedural NOP-LBBB also increased the risk of cardiac death and PPI within the year following the procedure. Further studies are urgently warranted to enhance preventive measures and optimize the management of conduction disturbances post-TAVR., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Aims: The aim of this study was to estimate the cost-effectiveness of transcatheter aortic valve implantation (TAVI) versus surgical aortic valve replacement (SAVR) in patients at lower surgical risk., Methods and Results: Discounted costs from a societal perspective and effectiveness as quality-adjusted life years (QALYs) were projected to lifetime via a decision-analytic model calibrated to 60-month data from the NOTION trial. The base case assumed a scenario in which any mortality benefit would gradually fade out over time, with other scenarios explored in sensitivity analyses. The incremental cost-effectiveness ratio (ICER) was compared to the country-specific willingness-to-pay (WTP) threshold of 1.13 million Danish kroner (DKK). The base case ICER was DKK 696,264/QALY (around €72,100/QALY via purchasing parity adjustment). Variation in long-term mortality beyond five years led to limited variation of incremental costs (DKK 64,200 to 64,600), but a more pronounced variation in incremental QALYs (0.07 to 0.19 QALYs for most conservative and optimistic assumptions, compared to base case of 0.09 QALYs). All resulting ICERs (range DKK 334,200 to DKK 904,100 per QALY gained) were below the WTP threshold., Conclusions: TAVI in a cohort of primarily low surgical risk patients was found to be a cost-effective treatment strategy in the Danish healthcare system. Cost-effectiveness analyses in other settings are warranted as are registries given the sensitivity of the model to long-term mortality.

Transcatheter aortic valve replacement (TAVR) is an established alternative to surgical valve replacement for patients with severe aortic stenosis (AS) and increased surgical risk. On the basis of the favorable outcomes of recent randomized clinical trials conducted in intermediate and low risk populations, TAVR is expected in the near future to be offered to patients not only at lower surgical risk, but also with longer life expectancy. In this particular subset, the long-term durability of the bioprosthetic valve is of critical importance. The European Association of Percutaneous Cardiovascular Interventions (EAPCI), the European Society of Cardiology (ESC), and the European Association for Cardio-Thoracic Surgery (EACTS) recently introduced standardized criteria to define structural valve deterioration (SVD) and valve failure of transcatheter and surgical aortic bioprosthesis-this with the aim to generate uniformity in data reporting in future studies assessing long-term durability of aortic bioprosthesis. On this background, the aim of this article is to review the definition, incidence and predictors of transcatheter bioprosthetic valve dysfunction, including structural and non-structural valve deterioration (SVD/NSVD), valve thrombosis, and endocarditis., (Copyright © 2019 Sawaya, Jørgensen, Søndergaard and De Backer.)

Background: The NOTION trial (Nordic Aortic Valve Intervention) was designed to compare transcatheter aortic valve replacement (TAVR) with surgical aortic valve replacement (SAVR) in patients ≥70 years old with isolated severe aortic valve stenosis. Clinical and echocardiographic outcomes are presented after 5 years., Methods: Patients were enrolled at 3 Nordic centers and randomized 1:1 to TAVR using the self-expanding CoreValve prosthesis (n=145) or SAVR using any stented bioprostheses (n=135). The primary composite outcome was the rate of all-cause mortality, stroke, or myocardial infarction at 1 year defined according to Valve Academic Research Consortium-2 criteria., Results: Baseline characteristics were similar. The mean age was 79.1±4.8 years and mean Society of Thoracic Surgeons Predicted Risk of Mortality score was 3.0%±1.7%. After 5 years, there were no differences between TAVR and SAVR in the composite outcome (Kaplan-Meier estimates 38.0% versus 36.3%, log-rank test P =0.86) or any of its components. TAVR patients had larger prosthetic valve area (1.7 cm 2 versus 1.2 cm 2 , P <0.001) with a lower mean transprosthetic gradient (8.2 mm Hg versus 13.7 mm Hg, P <0.001), both unchanged over time. More TAVR patients had moderate/severe total aortic regurgitation (8.2% versus 0.0%, P <0.001) and a new pacemaker (43.7% versus 8.7%, P <0.001). Four patients had prosthetic reintervention and no difference was found for functional outcomes., Conclusions: These are currently the longest follow-up data comparing TAVR and SAVR in lower risk patients, demonstrating no statistical difference for major clinical outcomes 5 years after TAVR with a self-expanding prosthesis compared to SAVR. Higher rates of prosthetic regurgitation and pacemaker implantation were seen after TAVR., Clinical Trial Registration: URL: https://clinicaltrials.gov. Unique identifier: NCT01057173.

Background: Transcatheter aortic valve replacement (TAVR) is an alternative to surgical aortic valve replacement (SAVR) in patients with severe aortic stenosis and intermediate or high surgical risk., Objectives: The aim of this study was to compare the durability of transcatheter and surgical bioprosthetic aortic valves using standardized criteria., Methods: In the NOTION (Nordic Aortic Valve Intervention) trial, all-comer patients with severe aortic stenosis and lower surgical risk for mortality were randomized 1:1 to TAVR (n = 139) or SAVR (n = 135). Moderate/severe structural valve deterioration (SVD) was defined as a mean gradient ≥20 mm Hg, an increase in mean gradient ≥10 mm Hg from 3 months post-procedure, or more than mild intraprosthetic aortic regurgitation (AR) either new or worsening from 3 months post-procedure. Nonstructural valve deterioration (NSVD) was defined as moderate/severe patient-prosthesis mismatch at 3 months or moderate/severe paravalvular leakage. Bioprosthetic valve failure (BVF) was defined as: valve-related death, aortic valve reintervention, or severe hemodynamic SVD., Results: At 6 years, the rates of all-cause mortality were similar for TAVR (42.5%) and SAVR (37.7%) patients (p = 0.58). The rate of SVD was higher for SAVR than TAVR (24.0% vs. 4.8%; p < 0.001), whereas there were no differences in NSVD (57.8% vs. 54.0%; p = 0.52) or endocarditis (5.9% vs. 5.8%; p = 0.95). BVF rates were similar after SAVR and TAVR through 6 years (6.7% vs. 7.5%; p = 0.89)., Conclusions: In the NOTION trial through 6 years, SVD was significantly greater for SAVR than TAVR, whereas BVF was low and similar for both groups. Longer-term follow-up of randomized clinical trials will be necessary to confirm these findings. (Nordic Aortic Valve Intervention Trial; NCT01057173)., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to assess mortality and rehospitalization in patients with new bundle branch block (BBB) and/or permanent pacemaker (PPM) after transcatheter aortic valve replacement (TAVR)., Background: Previous studies have provided inconsistent results on the clinical impact of new BBB or new PPM after TAVR., Methods: A total of 816 consecutive patients without pre-procedural BBB or PPM undergoing TAVR between 2007 and 2017 were followed for 5 years or until data extraction in September 2017. Data on vital status and hospitalization were obtained through national registries., Results: Within 30 days post-TAVR, new BBB without PPM and new PPM occurred in 247 (30.3%) and 132 (16.2%) patients, respectively, leaving 437 patients (53.6%) without conduction abnormalities. Median follow-up was 2.5 years (interquartile range: 1.0 to 4.9 years). One-year all-cause mortality was increased for new BBB (hazard ratio [HR]: 2.80; 95% confidence interval [CI]: 1.18 to 3.67) but not for new PPM (HR: 1.64; 95% CI: 0.72 to 3.74) compared with patients with no conduction abnormalities. The risk for late all-cause mortality (≥1 year after TAVR) was higher both for patients with new BBB (HR: 1.79; 95% CI: 1.24 to 2.59) and for those with new PPM (HR: 1.58; 95% CI: 1.01 to 2.46) compared with patients with no conduction abnormalities. Patients with new BBB (HR: 1.47; 95% CI: 1.02 to 2.12) and new PPM (HR: 1.66; 95% CI: 1.09 to 2.54) had a higher risk for heart failure hospitalization and reduced left ventricular ejection fraction (p < 0.0001 for both groups) during follow-up., Conclusions: New BBB and new PPM developed frequently after TAVR. New BBB was associated with increased early and late all-cause mortality, whereas new PPM was associated with late all-cause mortality. Furthermore, both new BBB and new PPM increased the risk for heart failure hospitalizations., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

During the latest decade, transcatheter aortic valve implantation (TAVI) has evolved from being indicated only in patients with severe aortic stenosis and prohibitive or high surgical risk, to be an alternative to surgical aortic valve replacement in patients with intermediate surgical risk. Improvements of the peri-procedural management have resulted in marked reduction of complications and an increasing number of patients treated with TAVI every year in Denmark. By a minimalist approach, TAVI can be performed in local anesthaesia, with same day mobilisation and discharge within few days, without affecting the safety.

Objectives: The aim of this study was to use a 12-lead electrocardiogram obtained immediately post-transcatheter aortic valve replacement (TAVR) to identify predictors of late high-degree conduction defect (HD-CD) within 30 days after TAVR., Background: There are limited data on risk factors for the development of late HD-CD and the need to retain the temporary pacemaker after TAVR., Methods: A single-center study was conducted including 467 consecutive patients, without pre-procedural pacemakers, undergoing TAVR., Results: Self-expandable, mechanical, or balloon-expandable heart valves were implanted in 328 (70%), 61 (13%), and 78 (17%) patients, respectively. For patients in sinus rhythm without right bundle branch block, late HD-CD developed in 0 of 70 patients (0%; 95% confidence interval [CI]: 0% to 5.1%) with PR interval <200 ms and QRS interval <120 ms and in 5 of 109 patients (4.6%; 95% CI: 1.5% to 10.4%; all with sufficient escape rhythm) with PR interval <240 ms and QRS interval <150 ms. Late HD-CD developed in 14 of 101 patients (13.9%; 95% CI: 7.8% to 22.2%; 6 with insufficient escape rhythm [5.9%; 95% CI: 2.2% to 12.5%]) with PR interval ≥240 ms or QRS interval ≥150 ms. Furthermore, late HD-CD developed in 3 of 49 patients (6.1%; 95% CI: 1.3% to 16.9%; all with sufficient escape rhythm) and in 3 of 30 patients (10.0%; 95% CI: 2.1% to 26.5%; 2 with insufficient escape rhythm [6.7%; 95% CI: 0.8% to 22.1%]) with atrial fibrillation and no right bundle branch block with QRS interval <140 and ≥140 ms, respectively., Conclusions: On the basis of immediate post-TAVR 12-lead electrocardiography, removing the temporary pacemaker immediately following TAVR is potentially safe in patients without right bundle branch block who are: 1) in sinus rhythm with PR interval <240 ms and QRS interval <150 ms; or 2) in atrial fibrillation with a QRS interval <140 ms., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Subclinical leaflet thrombosis of bioprosthetic aortic valves after transcatheter valve replacement (TAVR) and surgical aortic valve replacement (SAVR) has been found with CT imaging. The objective of this study was to report the prevalence of subclinical leaflet thrombosis in surgical and transcatheter aortic valves and the effect of novel oral anticoagulants (NOACs) on the subclinical leaflet thrombosis and subsequent valve haemodynamics and clinical outcomes on the basis of two registries of patients who had CT imaging done after TAVR or SAVR., Methods: Patients enrolled between Dec 22, 2014, and Jan 18, 2017, in the RESOLVE registry, and between June 2, 2014, and Sept 28, 2016, in the SAVORY registry, had CT imaging done with a dedicated four-dimensional volume-rendered imaging protocol at varying intervals after TAVR and SAVR. We defined subclinical leaflet thrombosis as the presence of reduced leaflet motion, along with corresponding hypoattenuating lesions shown with CT. We collected data for baseline demographics, antithrombotic therapy, and clinical outcomes. We analysed all CT scans, echocardiograms, and neurological events in a masked fashion., Findings: Of the 931 patients who had CT imaging done (657 [71%] in the RESOLVE registry and 274 [29%] in the SAVORY registry), 890 [96%] had interpretable CT scans (626 [70%] in the RESOLVE registry and 264 [30%] in the SAVORY registry). 106 (12%) of 890 patients had subclinical leaflet thrombosis, including five (4%) of 138 with thrombosis of surgical valves versus 101 (13%) of 752 with thrombosis of transcatheter valves (p=0·001). The median time from aortic valve replacement to CT for the entire cohort was 83 days (IQR 33-281). Subclinical leaflet thrombosis was less frequent among patients receiving anticoagulants (eight [4%] of 224) than among those receiving dual antiplatelet therapy (31 [15%] of 208; p<0·0001); NOACs were equally as effective as warfarin (three [3%] of 107 vs five [4%] of 117; p=0·72). Subclinical leaflet thrombosis resolved in 36 (100%) of 36 patients (warfarin 24 [67%]; NOACs 12 [33%]) receiving anticoagulants, whereas it persisted in 20 (91%) of 22 patients not receiving anticoagulants (p<0·0001). A greater proportion of patients with subclinical leaflet thrombosis had aortic valve gradients of more than 20 mm Hg and increases in aortic valve gradients of more than 10 mm Hg (12 [14%] of 88) than did those with normal leaflet motion (seven [1%] of 632; p<0·0001). Although stroke rates were not different between those with (4·12 strokes per 100 person-years) or without (1·92 strokes per 100 person-years) reduced leaflet motion (p=0·10), subclinical leaflet thrombosis was associated with increased rates of transient ischaemic attacks (TIAs; 4·18 TIAs per 100 person-years vs 0·60 TIAs per 100 person-years; p=0·0005) and all strokes or TIAs (7·85 vs 2·36 per 100 person-years; p=0·001)., Interpretation: Subclinical leaflet thrombosis occurred frequently in bioprosthetic aortic valves, more commonly in transcatheter than in surgical valves. Anticoagulation (both NOACs and warfarin), but not dual antiplatelet therapy, was effective in prevention or treatment of subclinical leaflet thrombosis. Subclinical leaflet thrombosis was associated with increased rates of TIAs and strokes or TIAs. Despite excellent outcomes after TAVR with the new-generation valves, prevention and treatment of subclinical leaflet thrombosis might offer a potential opportunity for further improvement in valve haemodynamics and clinical outcomes., Funding: RESOLVE (Cedars-Sinai Heart Institute) and SAVORY (Rigshospitalet)., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objectives: The aim of this study was to evaluate the use of transcatheter heart valves (THV) for the treatment of noncalcific pure native aortic valve regurgitation (NAVR) and failing bioprosthetic surgical heart valves (SHVs) with pure severe aortic regurgitation (AR)., Background: Limited data are available about the "off-label" use of transcatheter aortic valve replacement (TAVR) to treat pure severe AR., Methods: The study population consisted of patients with pure severe AR treated by TAVR at 18 different centers. Study endpoints were device success, early safety, and clinical efficacy at 30 days, as defined by Valve Academic Research Consortium 2 criteria., Results: A total of 146 patients were included, 78 patients in the NAVR group and 68 patients in the failing SHV group. In the NAVR group, device success, early safety, and clinical efficacy were 72%, 66%, and 61%, respectively. Device success and clinical efficacy were significantly better with newer generation THVs compared with old-generation THVs (85% vs. 54% and 75% vs. 46%, respectively, p < 0.05); this was mainly due to less second THV implantations and a lower rate of moderate to severe paravalvular regurgitation (10% vs. 24% and 3% vs. 27%, respectively). Independent predictors of 30-day mortality were body mass index <20 kg/m 2 , STS surgical risk score >8%, major vascular or access complication, and moderate to severe AR. In the failing SHV group, device success, early safety, and clinical efficacy were 71%, 90%, and 77%, respectively., Conclusions: TAVR for pure NAVR remains a challenging condition, with old-generation THVs being associated with THV embolization and migration and significant paravalvular regurgitation. Newer generation THVs show more promising outcomes. For those patients with severe AR due to failing SHVs, TAVR is a valuable therapeutic option., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Interventional cardiology in Denmark has been carried out since the mid 1980s. Interventional cardiology is only performed at a few high-volume centres. Healthcare coverage is universal and is essentially free of charge. Hospitals are mostly publicly owned and financed by fixed budgets and, in part, an activity-based funding system. Approximately 30,000 coronary angiographies (CAG), 10,000 percutaneous coronary interventions (PCIs) of which approximately 25% are primary PCIs, and 500 transcatheter aortic valve implantations (TAVIs) are carried out each year. The numbers of CAG and PCI have reached a plateau in recent years, whereas structural heart interventions, in particular TAVI, are increasing. Around 90% of all patients treated with PCI have a stent implanted, with more than 95% of these being drug-eluting stents. There is a low but increasing use of bioabsorbable scaffolds and drug-eluting balloons.

Background: Temporal development of new-onset atrial fibrillation (NOAF) after aortic valve replacement is unclear, and opportunistic screening has limited diagnostic accuracy. This is the first study to investigate the incidence and temporal development of NOAF detected by implantable loop recorder (ILR) in patients with aortic stenosis, randomized to surgical aortic valve replacement (SAVR) or transcatheter aortic valve replacement (TAVR)., Method: An ILR was implanted in a subgroup of patients without pre-procedural atrial fibrillation (AF), randomized to SAVR or TAVR in the NOTION trial. Data from the ILR were transmitted in intervals of 2weeks for 12weeks post-procedurally and analyzed., Results: The study included 25 and 27 patients who underwent SAVR and TAVR, respectively. The cumulative rate of NOAF was 100% and 81.5% for patients undergoing SAVR and TAVR, respectively (P=0.06). TAVR patients without NOAF 6weeks post-procedurally remained free from NOAF. The prevalence of AF after SAVR decreased significantly after 8weeks when compared with the first 2weeks (50.0% vs. 84.0%, respectively; P<0.05). The prevalence of AF after TAVR did not change significantly during follow-up. The median AF burden (percentage of time with AF) was 2.8% and 0.04% during the first 2weeks after SAVR and TAVR, respectively (P=0.01) and it decreased significantly over time after SAVR but not after TAVR., Conclusion: NOAF subsided 6weeks after TAVR. AF prevalence and burden decreased significantly over time after SAVR, but remained stable after TAVR. These findings may be considered for post-procedural anti-coagulation strategy., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Transcatheter aortic valve replacement (TAVR) has become an established therapeutic option for patients with symptomatic, severe aortic valve stenosis (AS) who are ineligible or at high risk for conventional valvular surgery. In Northwestern Europe, the TAVR technology is also increasingly used to treat patients with an intermediate risk profile., Methods and Results: The study was designed as an independent Nordic multicenter registry of intermediate risk patients treated with the Lotus Valve System (Boston Scientific, MA, USA; N=154). Valve Academic Research Consortium (VARC)-defined device success was obtained in 97.4%. A Lotus Valve was successfully implanted in all patients. There was no valve migration, embolization, ectopic valve deployment, or TAV-in-TAV deployment. The VARC-defined combined safety rate at 30days was 92.2%, with a mortality rate of 1.9% and stroke rate of 3.2%. The clinical efficacy rate after 30days was 91.6% - only one patient had moderate aortic regurgitation. When considering only those patients in the late experience group (N=79), the combined safety and clinical efficacy rates were 93.7% and 92.4%, respectively. The pacemaker implantation rate was 27.9% - this rate was 12.8% in case of a combined implantation depth <4mm and a device/annulus ratio<1.05., Conclusions: The present study demonstrates the efficacy and safety of the repositionable, retrievable Lotus Valve System in intermediate risk patients with AS. The VARC-defined device success rate was 97.4% with a 30-day patient safety and clinical efficacy rate of more than 90%. Less than moderate aortic regurgitation was obtained in 99.4% of patients., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Characterization of dense non-aqueous phase liquid (DNAPL) source zones in limestone aquifers/bedrock is essential to develop accurate site-specific conceptual models and perform risk assessment. Here innovative field methods were combined to improve determination of source zone architecture, hydrogeology and contaminant distribution. The FACT™ is a new technology and it was applied and tested at a contaminated site with a limestone aquifer, together with a number of existing methods including wire-line coring with core subsampling, FLUTe® transmissivity profiling and multilevel water sampling. Laboratory sorption studies were combined with a model of contaminant uptake on the FACT™ for data interpretation. Limestone aquifers were found particularly difficult to sample with existing methods because of core loss, particularly from soft zones in contact with chert beds. Water FLUTe™ multilevel groundwater sampling (under two flow conditions) and FACT™ sampling and analysis combined with FLUTe® transmissivity profiling and modeling were used to provide a line of evidence for the presence of DNAPL, dissolved and sorbed phase contamination in the limestone fractures and matrix. The combined methods were able to provide detailed vertical profiles of DNAPL and contaminant distributions, water flows and fracture zones in the aquifer and are therefore a powerful tool for site investigation. For the limestone aquifer the results indicate horizontal spreading in the upper crushed zone, vertical migration through fractures in the bryozoan limestone down to about 16-18m depth with some horizontal migrations along horizontal fractures within the limestone. Documentation of the DNAPL source in the limestone aquifer was significantly improved by the use of FACT™ and Water FLUTe™ data., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Surgical aortic valve replacement (SAVR) and, more recently, transcatheter aortic valve implantation (TAVI) have been shown to be the only treatments that can improve the natural cause of severe aortic valve stenosis. However, after SAVR and TAVI, the incidence of new-onset atrial fibrillation (NOAF) is 31%-64% and 4%-32%, respectively. NOAF is independently associated with adverse events such as stroke, death, and increased length of hospital stay. Increasing the knowledge of predisposing factors, optimal postprocedural monitoring, and prophylactic antiarrhythmic and antithrombotic therapy may reduce the risk of complications secondary to NOAF.